Antigen persistence in chronic infections and cancer up-regulates inhibitory networks, such as the PD-1 and IL-10 pathways, that impair immunity and lead to disease progression. These pathways are attractive targets for immunotherapy, as demonstrated by recent clinical trials of PD-1/PD-L1 blockade in cancer patients. However, in HIV-1 infection not all subjects respond to inhibition of either pathway and the mechanistic interactions between these two networks remain to be better defined. Here we demonstrate that in vitro blockade of PD-L1 and/or IL-10Rα results in markedly different profiles of HIV-1-specific CD4 T cell restoration. Whereas PD-L1 blockade leads to balanced increase in IFN-γ, IL-2 and IL-13 secretion, IL-10Rα blockade preferentially restores IFN-γ production. In viremic subjects, combined PD-L1/IL-10Rα blockade results in a striking 10-fold increase in IFN-γ secretion by HIV-1-specific CD4 T cells that is not observed in subjects with spontaneous (elite controllers) or therapy-induced control of viral replication. In contrast to the dramatic increase in IFN-γ, concurrent blockade has a marginal additive effect on IL-2 production, IL-13 secretion and HIV-1-specific CD4 T cell proliferation. IFN-γ produced by Thelper cells up-regulates PD-L1, HLA I/II and IL-12 expression by monocytes. The effect of combined blockade on IFN-γ was dependent on reciprocal reinforcement through IL-12. These studies provide crucial information on the different immunoregulatory qualities of PD-1 and IL-10 in progressive disease, and link exhausted virus-specific CD4 T cells and monocytes in the regulation of IFNγ and IL-12 secretion.